Subscribe to eTOC

TEMOZOLOMIDE CHEMOTHERAPY TRIAL SETS NEW STANDARD OF CARE FOR RECENTLY DIAGNOSED GLIOMAS

A phase III clinical trial has demonstrated a survival benefit when patients with newly diagnosed malignant gliomas are treated with temozolomide chemotherapy in addition to radiation.

Until now, the disease has progressed rapidly, despite aggressive treatment with conventional debulking surgery and postoperative radiation. Survival rarely lasts beyond one year, with few patients still alive at two years. Researchers have investigated a variety of chemotherapeutic agents, but temozolomide is the first agent to substantially impact on outcome.

SURVIVAL AT TWO YEARS

“Survival at two years was 26.5 percent in the group receiving adjuvant temozolomide with radiation compared with 10 percent for patients in the group getting radiation alone,” said Barbara Fisher, MD, a study co-investigator and neurologist at the University of Western Ontario in Ontario, Canada, in a telephone interview with Neurology Today.

At a follow-up of 28 months, the median survival was 14.6 months in the patients receiving adjuvant temozolomide therapy versus 12.1 months in those receiving radiation alone, she said. “The importance of the study is that everything we have tried hasn't worked,” said Dr. Fisher. “Now we finally have something that works. It is the new standard of care.”

The study team tested the protocol in patients between 18 and 74 years old with newly diagnosed and histologically confirmed glioma (World Health Organization grade IV astrocytoma).

The randomized trial of 573 patients from 85 centers in Europe and Canada had two treatment arms: those assigned to radiotherapy alone and those receiving radiotherapy plus temozolomide, given both concomitantly and after radiation therapy. Results from the trial, sponsored by the European Organization for Research and Treatment of Cancer Brain Tumours and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group, were published in the New England Journal of Medicine (2005;352:987–996).

Figure

Dr. Lisa DeAngelis: “If we are not going to use these therapies, what good is it?”

INVESTIGATING TEMOZOLOMIDE FURTHER

Besides setting a new standard of care for patients with newly diagnosed gliomas, Dr. Fisher said that the trial would serve as the springboard for molecular research that will home in on why it works. Additionally, other trials are on the drawing board that will examine the potential benefits of adjuvant temozolomide for other neuro-oncological cancers. She said that the agent might benefit patients with cancers, such as CNS lymphoma and anaplastic gliomas.

In a companion editorial, Lisa M. DeAngelis, MD, Chair of the Neurology Department at Memorial Sloan-Kettering Cancer Center in New York City, wrote that the study is a “substantial step forward in the field.”

In a telephone interview with Neurology Today, Dr. DeAngelis stressed that she worries that despite the trial demonstrating a prolonged survival for the vast majority of patients, “we need to make sure that it is incorporated as the standard of care for all patients”.

A survey by Susan Chang, MD, published earlier this year in JAMA (2005;293:557–564), reported that just over half of patients with malignant gliomas received chemotherapy and 88 percent of patients treated at 52 clinical sites received prophylactic anticonvulsants. The AAN clinical practice guidelines recommend chemotherapy and they advise against the use of prophylactic antiepileptics. “If we are not going to use these therapies [temozolomide], what good is it,” she said.

DEMOGRAPHIC CHARACTERISTICS

Other study findings revealed that the patient groups shared similar demographic characteristics. The median age of patients in the study was 56 years old and 84 percent had debulking surgery. Complete resections were performed in 40 percent of those in the radiotherapy group and 39 percent in the temozolomide combination regimen. Partial resections were performed in 45 percent of the radiotherapy group versus 44 percent in the radiotherapy plus temozolomide trial arm. WHO performance status ranged from 0 to 2 in both groups – 0 indicating being fully active and 2 indicating an ability to conduct self-care but being restricted in the ability to do work – with approximately 85 percent with a WHO performance status of 0 to 1. The median time from diagnosis to treatment was five weeks.

The only patient subgroups that did not show a benefit from temozolomide were those who had a biopsy only and those with a poor performance status. The results found that radiotherapy plus temozolomide had an acceptable safety profile. Four percent of patients had grade 3 or 4 neutropenia and 3 percent had grade 3 or 4 cytopenia.

STRATIFYING PATIENTS

Using the same data set, researchers conducted a subgroup analysis to determine whether the status of a specific molecular marker, MGMT, could help stratify patients most likely to benefit from temozolomide therapy. Results from the study appear in the same issue of the New England Journal of Medicine (2005;293:997–1003). Monika E. Hegi, PhD, from the Department of Tumor Biology and Genetics and Department of Neurosurgery at University Hospital in Lausanne, Switzerland, was the lead investigator on the study.

Investigators focused on MGMT promoter gene activity in cancer cells. Previous research has shown that high levels of MGMT in brain tumor cancer cells have a positive predictive value for overall survival. Conversely, when a process known as methylation turns off the MGMT promoter gene, patients have improved survival and a better response to chemotherapy.

Figure

Dr. Henry Friedman: “The big question is what are we going to do with patients who have a negative MGMT assay? If temozolomide alone doesnt work, are people going to take a step back?”

To assess the MGMT activity in tumor tissue, the research team used PCR staining techniques and evaluated 307 of 573 (53.6 percent) glioma specimens. Of these specimens, MGMT status could be determined for 206 patients. These specimens were representative of those in the overall treatment population.

GOOD NEWS FOR PATIENTS

Nearly half (45 percent) of specimens had a methylated gene. The study findings are good news for patients with malignant gliomas, commented Drs. DeAngelis and Fisher. It further validated that methylation was an independent positive predictor for survival. The association was positive for patients in both treatment arms, but it was stronger for patients on the radiotherapy plus temozolomide protocol after the first nine months of follow-up. In the first nine months, impact on outcome was similar.

The median overall survival for the entire patient population was 18.2 months among patients with a methylated MGMT promoter versus 12.2 months among patients who were MGMT negative. When treatment modality was taken into account, survival was approximately 1.5-fold higher (21.7 months) in the patients who were both MGMT positive and in the combination protocol versus 15.3 months among those receiving radiation alone. The authors write: “This suggests that MGMT methylation, though important, is not the sole factor determining outcome…Additional mechanisms and predictive factors are likely to be relevant and need to be identified.”

Dr. Henry Friedman, Co-director of the Neuro-oncology program at Duke University Medical Center, viewed the studies as a major advance after a decades-long hiatus in the field. “The big question is what are we going to do with patients who have a negative MGMT assay?” Henry Friedman, MD, told Neurology Today in a telephone interview. “If temozolomide alone doesn't work, are people going to take a step back?”

Further, Dr. Friedman said that the study has done a lot of service in helping to stratify patients. Also, he sees it as an entrée for examining multiple agent chemotherapy. “We are headed in the right direction,” he said. “The question is how much better can we do.”

ARTICLE IN BRIEF

  • ✓ A phase III clinical trial found that survival at two years for patients with malignant gliomas was 26.5 percent in patients receiving adjuvant temozolomide with radiation compared with 10 percent for patients in the group getting radiation alone.

REFERENCES

• Stupp, R, Mason, MP et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.
    • Hegi, ME, Diserens AC et al. MGMT gene silencing and benefit from temozolomide in gioblastoma. N Engl J Med 2005;352:997–1003.
      • DeAngelis LM. Chemotherapy for brain tumors –a new beginning. N Engl J Med 2005;352:1036–1037.
        • Chang SM, Parney IF, et al. Patterns of care for adults with newly diagnosed malignant glioma. JAMA 2005;293:557–664.